1.
Carl Ferdinand Cori
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In 2004 both were designated a National Historic Chemical Landmark in recognition of their work that elucidated carbohydrate metabolism. Carl was the son of Carl Isidor Cori, a zoologist, and Maria née Lippich, the Cori Family came from the Papal State to the Royal Bohemian Crownland, Austrian Circle at the end of the 17th century. Carl Ferdinands grandfather Eduard Cori was an officer and beekeeper in Brüx. Carl Ferdinands younger sister Margarete Cori was a lecturer of Prague and he grew up in Trieste, where his father Carl Isidor was the director of the Marine Biological Station. In late 1914 the Cori family moved to Prague and Carl entered the school of Charles University in Prague. While studying there he met Gerty Theresa Radnitz and he was drafted into the Austro-Hungarian Army and served in the ski corps, and later was transferred to the sanitary corps, for which he set up a laboratory in Trieste. At the end of the war Carl completed his studies, graduating with Gerty in 1920, Carl and Gerty married that year and worked together in clinics in Vienna. Carl was invited to Graz to work with Otto Loewi to study the effect of the vagus nerve on the heart, while Carl was in Graz, Gerty remained in Vienna. A year later Carl was offered a position at the State Institute for the Study of Malignant Diseases in Buffalo, New York, in 1928, they became naturalized citizens of the United States. While at the Institute the Coris’ research focused on carbohydrate metabolism, in 1931 Carl accepted a position at the Washington University School of Medicine in St. Louis, Missouri. Carl joined as professor of pharmacology and in 1942 was made professor of biochemistry, in St. Louis, the Coris continued their research on glycogen and glucose and began to describe glycogenolysis, identifying and synthesizing the important enzyme glycogen phosphorylase. For these discoveries, they received the Nobel Prize in Physiology or Medicine in 1947, Gerty died in 1957 and Carl married Anne Fitz-Gerald Jones in 1960. He stayed on at Washington University until 1966, when he retired as chair of the biochemistry department and he was appointed visiting professor of Biological Chemistry at Harvard University while maintaining a laboratory space at the Massachusetts General Hospital, where he pursued research in genetics. From 1968 to 1983 he collaborated with noted geneticist Salomé Glüecksohn-Waelsch of the Albert Einstein College of Medicine in New York, in 1976 Carl received the Laurea honoris causa in Medicine from the University of Trieste. Cori was elected a Foreign Member of the Royal Society in 1950 and the Carl Cori Endowed Professorship at Washington University is named in his honor, currently held by Colin Nichols
2.
Gerty Cori
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Gerty was not a nickname, but rather she was named after an Austrian warship. Because of deteriorating conditions in Europe, the couple emigrated to the United States in 1922, Gerty Cori continued her early interest in medical research, collaborating in the laboratory with Carl. She published research findings coauthored with her husband, as well as publishing singly, unlike her husband, she had difficulty securing research positions, and the ones she obtained provided meager pay. Her husband insisted on continuing their collaboration, though he was discouraged from doing so by the institutions that employed him and they also identified the important catalyzing compound, the Cori ester. In 2004, both Gerty and Carl Cori were designated a National Historic Chemical Landmark in recognition of their work in clarifying carbohydrate metabolism, in 1957, Gerty Cori died after a ten-year struggle with myelosclerosis. She remained active in the laboratory until the end. She received recognition for her achievements through multiple awards and honors, the Cori crater on the Moon and the Cori crater on Venus are named after her. Gerty Theresa Radnitz was born into a Jewish family in Prague in 1896 and her father, Otto Radnitz, was a chemist who became manager of sugar refineries after inventing a successful method for refining sugar. Her mother, Martha, a friend of Franz Kafka, was a sophisticated woman. Gerty was tutored at home before enrolling in a Lyceum for girls, pursuing the study of science, Gerty learned that she lacked the prerequisites in Latin, physics, chemistry, and mathematics. Over the course of a year, she managed to study the equivalent of eight years of Latin, five years of science and her uncle, a professor of pediatrics, encouraged her to attend medical school, so she studied for and passed the University entrance examination. She was admitted to the school of the Karl-Ferdinands-Universität in Prague in 1914. While studying she met Carl Cori who was attracted to her charm, vitality, sense of humor and her love of the outdoors. Gerty and Carl had both entered medical school at eighteen and both graduated in 1920, Gerty converted to Catholicism, enabling her and Carl to marry in the Roman Catholic Church. They moved to Vienna, Austria, where Gerty spent the two years at the Carolinen Childrens Hospital, and her husband worked in a laboratory. Carl served in the Austrian army during World War I after being drafted, life was difficult following World War I, and Gerty suffered from xerophthalmia caused by severe malnutrition due to food shortages. These problems, in conjunction with the increasing anti-Semitism, contributed to the Coris decision to leave Europe, in 1922, the Coris both immigrated to the United States to pursue medical research at the State Institute for the Study of Malignant Diseases in Buffalo, New York. In 1928, they became naturalized citizens of the United States, the director for the Institute threatened to dismiss Gerty if she did not cease collaborative research with her husband
3.
Lactic acid
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Lactic acid is an organic compound with the formula CH3CHCO2H. In its solid state, it is white and water-soluble, in its liquid state, it is clear. It is produced naturally and synthetically. With a hydroxyl group adjacent to the group, lactic acid is classified as an alpha-hydroxy acid. In the form of its base called lactate, it plays a role in several biochemical processes. In solution, it can ionize a proton from the carboxyl group, compared to acetic acid, its pKa is 1 unit less, meaning lactic acid deprotonates ten times more easily than acetic acid does. This higher acidity is the consequence of the hydrogen bonding between the α-hydroxyl and the carboxylate group. Lactic acid is chiral, consisting of two optical isomers, one is known as L--lactic acid or -lactic acid and the other, its mirror image, is D--lactic acid or -lactic acid. A mixture of the two in equal amounts is called DL-lactic acid, or racemic lactic acid, DL-lactic acid is miscible with water and with ethanol above its melting point which is around 17 or 18 °C. D-lactic acid and L-lactic acid have a melting point. In animals, L-lactate is constantly produced from pyruvate via the enzyme lactate dehydrogenase in a process of fermentation during normal metabolism and exercise. The concentration of lactate is usually 1–2 mmol/L at rest. In industry, lactic acid fermentation is performed by lactic acid bacteria and these bacteria can also grow in the mouth, the acid they produce is responsible for the tooth decay known as caries. In medicine, lactate is one of the components of lactated Ringers solution. These intravenous fluids consist of sodium and potassium cations along with lactate and chloride anions in solution with distilled water and it is most commonly used for fluid resuscitation after blood loss due to trauma, surgery, or burns. Lactic acid was isolated for the first time by the Swedish chemist Carl Wilhelm Scheele in 1780 from sour milk, the name reflects the lact- combining form derived from the Latin word for milk. In 1808, Jöns Jacob Berzelius discovered that lactic acid also is produced in muscles during exertion and its structure was established by Johannes Wislicenus in 1873. In 1856, Louis Pasteur discovered Lactobacillus and its role in the making of lactic acid, lactic acid started to be produced commercially by the German pharmacy Boehringer Ingelheim in 1895
4.
Glycolysis
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Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+. The free energy released in this process is used to form the high-energy molecules ATP, glycolysis is a determined sequence of ten enzyme-catalyzed reactions. The intermediates provide entry points to glycolysis, for example, most monosaccharides, such as fructose and galactose, can be converted to one of these intermediates. The intermediates may also be directly useful, for example, the intermediate dihydroxyacetone phosphate is a source of the glycerol that combines with fatty acids to form fat. Glycolysis is an oxygen independent metabolic pathway, meaning that it not use molecular oxygen for any of its reactions. However the products of glycolysis are sometimes metabolized using atmospheric oxygen, when molecular oxygen is used for the metabolism of the products of glycolysis the process is usually referred to as aerobic, whereas if no oxygen is used the process is said to be anaerobic. Thus, glycolysis occurs, with variations, in all organisms. The wide occurrence of glycolysis indicates that it is one of the most ancient metabolic pathways, glycolysis could thus have originated from chemical constraints of the prebiotic world. Glycolysis occurs in most organisms in the cytosol of the cell, the most common type of glycolysis is the Embden–Meyerhof–Parnas, which was discovered by Gustav Embden, Otto Meyerhof, and Jakub Karol Parnas. Glycolysis also refers to other pathways, such as the Entner–Doudoroff pathway, however, the discussion here will be limited to the Embden–Meyerhof–Parnas pathway. The overall reaction of glycolysis is, The use of symbols in this equation makes it appear unbalanced with respect to oxygen atoms, hydrogen atoms, and charges. In the cellular environment, all three groups of ADP dissociate into −O− and H+, giving ADP3−, and this ion tends to exist in an ionic bond with Mg2+. ATP behaves identically except that it has four groups, giving ATPMg2−. When these differences along with the charges on the two phosphate groups are considered together, the net charges of −4 on each side are balanced. For simple fermentations, the metabolism of one molecule of glucose to two molecules of pyruvate has a net yield of two molecules of ATP, most cells will then carry out further reactions to repay the used NAD+ and produce a final product of ethanol or lactic acid. Many bacteria use inorganic compounds as hydrogen acceptors to regenerate the NAD+, cells performing aerobic respiration synthesize much more ATP, but not as part of glycolysis. These further aerobic reactions use pyruvate and NADH + H+ from glycolysis, the pathway of glycolysis as it is known today took almost 100 years to fully discover. The combined results of many experiments were required in order to understand the pathway as a whole
5.
Nobel Prize in Physiology or Medicine
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The Nobel Prize in Physiology or Medicine, administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the fields of life sciences and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, Nobel was personally interested in experimental physiology and wanted to establish a prize for progress through scientific discoveries in laboratories. The Nobel Prize is presented to the recipient at a ceremony on 10 December, the anniversary of Nobels death, along with a diploma. The front side of the medal provides the profile of Alfred Nobel as depicted on the medals for Physics, Chemistry. As of 2015,106 Nobel Prizes in Physiology or Medicine have been awarded to 198 men and 12 women. The first Nobel Prize in Physiology or Medicine was awarded in 1901 to the German physiologist Emil von Behring, for his work on serum therapy and this includes one to António Egas Moniz in 1949 for the prefrontal leucotomy, bestowed despite protests from the medical establishment. Other controversies resulted from disagreements over who was included in the award, the 1952 prize to Selman Waksman was litigated in court, and half the patent rights awarded to his co-discoverer Albert Schatz who was not recognized by the prize. The 1962 prize awarded to James D, since the Nobel Prize rules forbid nominations of the deceased, longevity is an asset, one prize being awarded as long as 50 years after the discovery. Alfred Nobel was born on 21 October 1833 in Stockholm, Sweden into a family of engineers and he was a chemist, engineer and inventor who amassed a fortune during his lifetime, most of it from his 355 inventions of which dynamite is the most famous. He was interested in experimental physiology and set up his own labs in France, in 1888, Nobel was surprised to read his own obituary, titled The merchant of death is dead, in a French newspaper. Though Nobel wrote several wills during his lifetime, the last was written a little over a year before he died at the age of 63, because his will was contested, it was not approved by the Storting until 26 April 1897. After Nobels death, the Nobel Foundation was set up to manage the assets of the bequest, in 1900, the Nobel Foundations newly created statutes were promulgated by Swedish King Oscar II. According to Nobels will, the Karolinska Institutet in Sweden, a medical school, today, the prize is commonly referred to as the Nobel Prize in Medicine. It was important to Nobel that the prize be awarded for a discovery, per the provisions of the will, only select persons are eligible to nominate individuals for the award. Past Nobel laureates may also nominate, until 1977, all professors of Karolinska Institutet together decided on the Nobel Prize in Physiology or Medicine. Therefore, the Nobel Assembly was constituted, consisting of 50 professors at Karolinska Institutet. It elects the Nobel Committee with 5 members who evaluate the nominees, the Secretary who is in charge of the organization, in 1968, a provision was added that no more than three persons may share a Nobel prize. True to its mandate, the Committee has selected researchers working in the sciences over those who have made applied contributions
6.
Adenosine triphosphate
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Adenosine triphosphate is a nucleotide, also called a nucleoside triphosphate, is a small molecule used in cells as a coenzyme. It is often referred to as the unit of currency of intracellular energy transfer. ATP transports chemical energy within cells for metabolism, most cellular functions need energy in order to be carried out, synthesis of proteins, synthesis of membranes, movement of the cell, cellular division, transport of various solutes etc. The ATP is the molecule that carries energy to the place where the energy is needed, when ATP breaks into ADP and Pi, the breakdown of the last covalent link of phosphate liberates energy that is used in reactions where it is needed. Substrate-level phosphorylation, oxidative phosphorylation in cellular respiration, and photophosphorylation in photosynthesis are three mechanisms of ATP biosynthesis. Metabolic processes that use ATP as an energy source convert it back into its precursors, ATP is therefore continuously recycled in organisms, the human body, which on average contains only 250 grams of ATP, turns over its own body weight equivalent in ATP each day. ATP is used as a substrate in signal transduction pathways by kinases that phosphorylate proteins and it is also used by adenylate cyclase, which uses ATP to produce the second messenger molecule cyclic AMP. The ratio between ATP and AMP is used as a way for a cell to sense how much energy is available and control the metabolic pathways that produce and consume ATP. Apart from its roles in signaling and energy metabolism, ATP is also incorporated into nucleic acids by polymerases in the process of transcription, ATP is the neurotransmitter believed to signal the sense of taste. The structure of this consists of a purine base attached by the 9′ nitrogen atom to the 1′ carbon atom of a pentose sugar. Three phosphate groups are attached at the 5′ carbon atom of the pentose sugar and it is the addition and removal of these phosphate groups that inter-convert ATP, ADP and AMP. When ATP is used in DNA synthesis, the sugar is first converted to deoxyribose by ribonucleotide reductase. ATP was discovered in 1929 by Karl Lohmann, and independently by Cyrus Fiske and Yellapragada Subbarow of Harvard Medical School and it was proposed to be the intermediary molecule between energy-yielding and energy-requiring reactions in cells by Fritz Albert Lipmann in 1941. It was first artificially synthesized by Alexander Todd in 1948, ATP consists of adenosine – composed of an adenine ring and a ribose sugar – and three phosphate groups. The phosphoryl groups, starting with the group closest to the ribose, are referred to as the alpha, beta, consequently, it is closely related to the adenosine nucleotide, a monomer of RNA. ATP is highly soluble in water and is stable in solutions between pH6.8 and 7.4, but is rapidly hydrolysed at extreme pH. Consequently, ATP is best stored as an anhydrous salt, ATP is an unstable molecule in unbuffered water, in which it hydrolyses to ADP and phosphate. This is because the strength of the bonds between the groups in ATP is less than the strength of the hydrogen bonds, between its products, and water
7.
Glycogen
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Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in humans, animals, and fungi. The polysaccharide structure represents the main form of glucose in the body. In humans, glycogen is made and stored primarily in the cells of the liver, glycogen functions as the secondary long-term energy storage, with the primary energy stores being fats held in adipose tissue. Muscle glycogen is converted into glucose by muscle cells, and liver glycogen converts to glucose for use throughout the body including the nervous system. Glycogen is the analogue of starch, a polymer that functions as energy storage in plants. It has a similar to amylopectin, but is more extensively branched. Both are white powders in their dry state, glycogen is found in the form of granules in the cytosol/cytoplasm in many cell types, and plays an important role in the glucose cycle. Glycogen forms a reserve that can be quickly mobilized to meet a sudden need for glucose. In the liver, glycogen can make up from 5–6% of the fresh weight. Only the glycogen stored in the liver can be accessible to other organs. In the muscles, glycogen is found in a low concentration, the amount of glycogen stored in the body—especially within the muscles, liver, and red blood cells—mostly depends on physical training, basal metabolic rate, and eating habits. Small amounts of glycogen are found in the kidneys, and even smaller amounts in certain cells in the brain. The uterus also stores glycogen during pregnancy to nourish the embryo, glycogen is a branched biopolymer consisting of linear chains of glucose residues with further chains branching off every 8 to 12 glucoses or so. Glucoses are linked together linearly by α glycosidic bonds from one glucose to the next, branches are linked to the chains from which they are branching off by α glycosidic bonds between the first glucose of the new branch and a glucose on the stem chain. Due to the way glycogen is synthesised, every glycogen granule has at its core a glycogenin protein. Glycogen in muscle, liver, and fat cells is stored in a hydrated form, as a meal containing carbohydrates or protein is eaten and digested, blood glucose levels rise, and the pancreas secretes insulin. Blood glucose from the vein enters liver cells. Insulin acts on the hepatocytes to stimulate the action of several enzymes, glucose molecules are added to the chains of glycogen as long as both insulin and glucose remain plentiful
8.
Skeletal muscle
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Skeletal muscle is one of three major muscle types, the others being cardiac muscle and smooth muscle. It is a form of striated muscle tissue which is under the control of the somatic nervous system. Most skeletal muscles are attached to bones by bundles of collagen fibers known as tendons, a skeletal muscle refers to multiple bundles of cells called muscle fibers. The fibres and muscles are surrounded by connective tissue layers called fasciae, Muscle fibres, or muscle cells, are formed from the fusion of developmental myoblasts in a process known as myogenesis. Muscle fibres are cylindrical, and have more than one nucleus, Muscle fibers are in turn composed of myofibrils. The myofibrils are composed of actin and myosin filaments, repeated in units called sarcomeres, the sarcomere is responsible for the striated appearance of skeletal muscle, and forms the basic machinery necessary for muscle contraction. Connective tissue is present in all muscles as fascia, Muscle fibres are the individual contractile units within muscle. A single muscle such as the biceps contains many muscle fibres, another group of cells, the myosatellite cells are found between the basement membrane and the sarcolemma of muscle fibers. These cells are normally quiescent but can be activated by exercise or pathology to provide additional myonuclei for muscle growth or repair, development Individual muscle fibers are formed during development from the fusion of several undifferentiated immature cells known as myoblasts into long, cylindrical, multi-nucleated cells. Differentiation into this state is completed before birth with the cells continuing to grow in size thereafter. Microanatomy Skeletal muscle exhibits a distinctive banding pattern when viewed under the due to the arrangement of cytoskeletal elements in the cytoplasm of the muscle fibers. The principal cytoplasmic proteins are myosin and actin which are arranged in a unit called a sarcomere. The interaction of myosin and actin is responsible for muscle contraction, every single organelle and macromolecule of a muscle fiber is arranged to ensure form meets function. The cell membrane is called the sarcolemma with the known as the sarcoplasm. In the sarcoplasm are the myofibrils, the myofibrils are long protein bundles about 1 micrometer in diameter each containing myofilaments. Pressed against the inside of the sarcolemma are the unusual flattened myonuclei, between the myofibrils are the mitochondria. While the muscle fiber does not have a smooth endoplasmic reticulum, the sarcoplasmic reticulum surrounds the myofibrils and holds a reserve of the calcium ions needed to cause a muscle contraction. Periodically, it has dilated end sacs known as terminal cisternae and these cross the muscle fiber from one side to the other
9.
Glycogenolysis
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Glycogenolysis is the breakdown of glycogen to glucose-6-phosphate and glycogen. Glycogen branches are catabolized by the removal of glucose monomers via phosphorolysis. Glucose-1-phosphate is converted to glucose-6-phosphate by the enzyme phosphoglucomutase, glucose residues are phosphorolysed from branches of glycogen until four residues before a glucose that is branched with a α linkage. Glycogen debranching enzyme then transfers three of the remaining four units to the end of another glycogen branch. This exposes the α branching point, which is hydrolysed by α glucosidase, removing the final glucose residue of the branch as a molecule of glucose and this is the only case in which a glycogen metabolite is not glucose-1-phosphate. The glucose is subsequently phosphorylated to glucose-6-phosphate by hexokinase, Glycogenolysis takes place in the cells of the muscle and liver tissues in response to hormonal and neural signals. In particular, glycogenolysis plays an important role in the fight-or-flight response, in myocytes, glycogen degradation serves to provide an immediate source of glucose-6-phosphate for glycolysis, to provide energy for muscle contraction. In hepatocytes, the purpose of the breakdown of glycogen is for the release of glucose into the bloodstream for uptake by other cells. Glycogenolysis is regulated hormonally in response to blood sugar levels by glucagon and insulin, in myocytes, glycogen degradation may also be stimulated by neural signals. Parenteral administration of glucagon is a human medical intervention in diabetic emergencies when sugar cannot be given orally. It can also be administered intramuscularly, mutations at the liver enzyme glycogen phosphorylase lead to glycogen storage disease VI. Mutations at the enzyme glycogen phosphorylase lead to McArdles disease. Deficiencies at the glycogen debranching enzyme lead to glycogen storage disease III, glycogenesis The chemical logic of glycogen degradation at ufp. pt Glycogenolysis at the US National Library of Medicine Medical Subject Headings
10.
Myocyte
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Skeletal muscle is one of three major muscle types, the others being cardiac muscle and smooth muscle. It is a form of striated muscle tissue which is under the control of the somatic nervous system. Most skeletal muscles are attached to bones by bundles of collagen fibers known as tendons, a skeletal muscle refers to multiple bundles of cells called muscle fibers. The fibres and muscles are surrounded by connective tissue layers called fasciae, Muscle fibres, or muscle cells, are formed from the fusion of developmental myoblasts in a process known as myogenesis. Muscle fibres are cylindrical, and have more than one nucleus, Muscle fibers are in turn composed of myofibrils. The myofibrils are composed of actin and myosin filaments, repeated in units called sarcomeres, the sarcomere is responsible for the striated appearance of skeletal muscle, and forms the basic machinery necessary for muscle contraction. Connective tissue is present in all muscles as fascia, Muscle fibres are the individual contractile units within muscle. A single muscle such as the biceps contains many muscle fibres, another group of cells, the myosatellite cells are found between the basement membrane and the sarcolemma of muscle fibers. These cells are normally quiescent but can be activated by exercise or pathology to provide additional myonuclei for muscle growth or repair, development Individual muscle fibers are formed during development from the fusion of several undifferentiated immature cells known as myoblasts into long, cylindrical, multi-nucleated cells. Differentiation into this state is completed before birth with the cells continuing to grow in size thereafter. Microanatomy Skeletal muscle exhibits a distinctive banding pattern when viewed under the due to the arrangement of cytoskeletal elements in the cytoplasm of the muscle fibers. The principal cytoplasmic proteins are myosin and actin which are arranged in a unit called a sarcomere. The interaction of myosin and actin is responsible for muscle contraction, every single organelle and macromolecule of a muscle fiber is arranged to ensure form meets function. The cell membrane is called the sarcolemma with the known as the sarcoplasm. In the sarcoplasm are the myofibrils, the myofibrils are long protein bundles about 1 micrometer in diameter each containing myofilaments. Pressed against the inside of the sarcolemma are the unusual flattened myonuclei, between the myofibrils are the mitochondria. While the muscle fiber does not have a smooth endoplasmic reticulum, the sarcoplasmic reticulum surrounds the myofibrils and holds a reserve of the calcium ions needed to cause a muscle contraction. Periodically, it has dilated end sacs known as terminal cisternae and these cross the muscle fiber from one side to the other
11.
Pyruvate
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Pyruvic acid is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the base, CH3COCOO−, is a key intermediate in several metabolic pathways. Pyruvic acid can be made from glucose through glycolysis, converted back to carbohydrates via gluconeogenesis and it can also be used to construct the amino acid alanine and can be converted into ethanol or lactic acid via fermentation. Pyruvic acid supplies energy to cells through the citric acid cycle when oxygen is present, pyruvic acid is a colorless liquid with a smell similar to that of acetic acid and is miscible with water. It is the output of the metabolism of known as glycolysis. One molecule of glucose breaks down into two molecules of pyruvate, which are used to provide further energy, in one of two ways. Pyruvate is converted into acetyl-coenzyme A, which is the input for a series of reactions known as the Krebs cycle. Pyruvate is also converted to oxaloacetate by an reaction, which replenishes Krebs cycle intermediates, also. These reactions are named after Hans Adolf Krebs, the biochemist awarded the 1953 Nobel Prize for physiology, jointly with Fritz Lipmann, for research into metabolic processes. The cycle is known as the citric acid cycle or tricarboxylic acid cycle. If insufficient oxygen is available, the acid is broken down anaerobically, creating lactate in animals and ethanol in plants, Pyruvate is a key intersection in the network of metabolic pathways. Pyruvate can be converted into carbohydrates via gluconeogenesis, to fatty acids or energy through acetyl-CoA, to the amino acid alanine, therefore, it unites several key metabolic processes. In glycolysis, phosphoenolpyruvate is converted to pyruvate by pyruvate kinase and this reaction is strongly exergonic and irreversible, in gluconeogenesis, it takes two enzymes, pyruvate carboxylase and PEP carboxykinase, to catalyze the reverse transformation of pyruvate to PEP. Compound C00074 at KEGG Pathway Database, enzyme 2.7.1.40 at KEGG Pathway Database. Compound C00022 at KEGG Pathway Database, click on genes, proteins and metabolites below to link to respective articles. Pyruvate decarboxylation by the pyruvate dehydrogenase complex produces acetyl-CoA, carboxylation by pyruvate carboxylase produces oxaloacetate. Transamination by alanine transaminase produces alanine, reduction by lactate dehydrogenase produces lactate. Pyruvate is sold as a supplement, though evidence supporting this use is lacking
12.
Citric acid cycle
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Its central importance to many biochemical pathways suggests that it was one of the earliest established components of cellular metabolism and may have originated abiogenically. The name of this pathway is derived from citric acid that is consumed. In addition, the cycle consumes acetate and water, reduces NAD+ to NADH, the NADH generated by the TCA cycle is fed into the oxidative phosphorylation pathway. The net result of two closely linked pathways is the oxidation of nutrients to produce usable chemical energy in the form of ATP. In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion, components of the TCA cycle were derived from anaerobic bacteria, and the TCA cycle itself may have evolved more than once. Theoretically there are alternatives to the TCA cycle, however. If several TCA alternatives had evolved independently, they all appear to have converged to the TCA cycle, the citric acid cycle is a key metabolic pathway that connects carbohydrate, fat, and protein metabolism. The reactions of the cycle are carried out by 8 enzymes that completely oxidize acetate, in the form of acetyl-CoA, through catabolism of sugars, fats, and proteins, the two-carbon organic product acetyl-CoA is produced which enters the citric acid cycle. The NADH and FADH2 generated by the citric acid cycle are in used by the oxidative phosphorylation pathway to generate energy-rich adenosine triphosphate. Acetyl-CoA may also be obtained from the oxidation of fatty acids, the citrate then goes through a series of chemical transformations, losing two carboxyl groups as CO2. The carbons lost as CO2 originate from what was oxaloacetate, not directly from acetyl-CoA, the carbons donated by acetyl-CoA become part of the oxaloacetate carbon backbone after the first turn of the citric acid cycle. Loss of the acetyl-CoA-donated carbons as CO2 requires several turns of the citric acid cycle. However, because of the role of the citric acid cycle in anabolism, they not be lost. Most of the energy available by the oxidative steps of the cycle is transferred as energy-rich electrons to NAD+. For each acetyl group that enters the citric cycle, three molecules of NADH are produced. Electrons are also transferred to the electron acceptor Q, forming QH2, at the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues. Two carbon atoms are oxidized to CO2, the energy from these reactions is transferred to other processes through GTP. The NADH generated in the TCA cycle may later be oxidized to drive ATP synthesis in a type of process called oxidative phosphorylation, FADH2 is covalently attached to succinate dehydrogenase, an enzyme which functions both in the CAC and the mitochondrial electron transport chain in oxidative phosphorylation
13.
Anaerobic metabolism
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Fermentation is a metabolic process that converts sugar to acids, gases, or alcohol. It occurs in yeast and bacteria, and also in oxygen-starved muscle cells, Fermentation is also used more broadly to refer to the bulk growth of microorganisms on a growth medium, often with the goal of producing a specific chemical product. French microbiologist Louis Pasteur is often remembered for his insights into fermentation, the science of fermentation is known as zymology. Fermentation takes place when the transport chain is unusable. In this case it becomes the primary means of ATP production. Fermentation turns NADH and pyruvate produced in glycolysis into NAD+. In the presence of O2, NADH and pyruvate are used to generate ATP in respiration and this is called oxidative phosphorylation, and it generates much more ATP than glycolysis alone. For that reason, cells generally benefit from avoiding fermentation when oxygen is available, the exception being obligate anaerobes which cannot tolerate oxygen. The first step, glycolysis, is common to all fermentation pathways, two ADP molecules and two Pi are converted to two ATP and two water molecules via substrate-level phosphorylation. Two molecules of NAD+ are also reduced to NADH, in oxidative phosphorylation the energy for ATP formation is derived from an electrochemical proton gradient generated across the inner mitochondrial membrane via the electron transport chain. Humans have used fermentation to produce drinks and beverages since the Neolithic age, Fermentation can even occur within the stomachs of animals, such as humans. To many people, fermentation simply means the production of alcohol, grains and fruits are fermented to produce beer, if a food soured, one might say it was off or fermented. Here are some definitions of fermentation and they range from informal, general usage to more scientific definitions. Preservation methods for food via microorganisms, any process that produces alcoholic beverages or acidic dairy products. Any large-scale microbial process occurring with or without air, any energy-releasing metabolic process that takes place only under anaerobic conditions. Fermentation does not necessarily have to be carried out in an anaerobic environment, for example, even in the presence of abundant oxygen, yeast cells greatly prefer fermentation to aerobic respiration, as long as sugars are readily available for consumption. The antibiotic activity of hops also inhibits aerobic metabolism in yeast, Fermentation reacts NADH with an endogenous, organic electron acceptor. Usually this is formed from the sugar during the glycolysis step. Sugars are the most common substrate of fermentation, and typical examples of products are ethanol, lactic acid, carbon dioxide
14.
Lactic acid fermentation
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Lactic acid fermentation is a metabolic process by which glucose and other six-carbon sugars are converted into cellular energy and the metabolite lactate. It is a fermentation reaction that occurs in some bacteria and animal cells. Sometimes even when oxygen is present and aerobic metabolism is happening in the mitochondria, if pyruvate is building up faster than it can be metabolized, lactate dehydrogenase catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of NADH and NAD+. In homolactic fermentation, one molecule of glucose is converted to two molecules of lactic acid. Heterolactic fermentation, in contrast, yields carbon dioxide and ethanol in addition to lactic acid, lactic acid fermentation is used in many areas of the world to produce foods that cannot be produced through other methods. The most commercially important genus of lactic acid-fermenting bacteria is Lactobacillus, though other bacteria, two of the most common applications of lactic acid fermentation are in the production of yogurt and sauerkraut. Kimchi also uses lactic acid fermentation, lactic acid fermentation is also used in the production of sauerkraut. The main type of bacteria used in the production of sauerkraut is of the genus Leuconostoc, as in yogurt, when the acidity rises due to lactic acid-fermenting organisms, many other pathogenic microorganisms are killed. The bacteria produce acid, as well as simple alcohols. These may then combine to form esters, contributing to the flavor of sauerkraut. Lactic acid is a component in the production of sour beers, including Lambics, the main method of producing yogurt is through the lactic acid fermentation of milk with harmless bacteria. The primary bacteria used are typically Lactobacillus bulgaricus and Streptococcus thermophilus and these bacteria produce lactic acid in the milk culture, decreasing its pH and causing it to congeal. The bacteria also produce compounds that give yogurt its distinctive flavor, an additional effect of the lowered pH is the incompatibility of the acidic environment with many other types of harmful bacteria. For a probiotic yogurt, additional types of such as Lactobacillus acidophilus are also added to the culture. Lactobacillus fermentation and accompanying production of acid provides a protective vaginal microbiome that protects against the proliferation of pathogenic organisms
15.
Lactate dehydrogenase
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Lactate dehydrogenase is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvic acid and back, as it converts NAD+ to NADH, a dehydrogenase is an enzyme that transfers a hydride from one molecule to another. LDH exist in four distinct enzyme classes and this article is specifically about the NAD-dependent L-lactate dehydrogenase. Other LDHs act on D-lactate and/or are dependent on cytochrome c, D-lactate dehydrogenase ), LDH is expressed extensively in body tissues, such as blood cells and heart muscle. Because it is released during tissue damage, it is a marker of common injuries, Lactate dehydrogenase catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of NADH and NAD+. It converts pyruvate, the product of glycolysis, to lactate when oxygen is absent or in short supply. At high concentrations of lactate, the enzyme exhibits feedback inhibition, and it also catalyzes the dehydrogenation of 2-Hydroxybutyrate, but it is a much poorer substrate than lactate. LDH in humans uses His as the acceptor, and works in unison with the coenzyme. The His active site, is not only found in the form of LDH. The noticeable difference between the two subunits that make up LDHs tertiary structure is the replacement of alanine with a glutamine, Lactate dehydrogenase is composed of four subunits. The two most common subunits are the LDH-M and LDH-H protein, encoded by the LDHA and LDHB genes and these two subunits can form five possible tetramers, 4H, 4M, and the three mixed tetramers. LDH-1 —in the heart and in RBC, as well as the brain, LDH-2 —in the reticuloendothelial system LDH-3 —in the lungs LDH-4 —in the kidneys, placenta, and pancreas LDH-5 —in the liver and striated muscle Usually LDH-2 is the predominant form in the serum. A LDH-1 level higher than the LDH-2 level suggests myocardial infarction, the use of this phenomenon to diagnose infarction has been largely superseded by the use of Troponin I or T measurement. There are two more mammalian LDH subunits that can be included in LDH tetramers, LDHC and LDHBx, LDHC is a testes-specific LDH protein, that is encoded by the LDHC gene. LDHBx is a peroxisome-specific LDH protein, LDHBx is the readthrough-form of LDHB. LDHBx is generated by translation of the LDHB mRNA, but the stop codon is interpreted as an amino acid-encoding codon, in consequence, translation continues to the next stop codon. This leads to the addition of seven amino acids to the normal LDH-H protein. The extension contains a peroxisomal targeting signal, so that LDHBx is imported into the peroxisome, the family also contains L-lactate dehydrogenases that catalyse the conversion of L-lactate to pyruvate, the last step in anaerobic glycolysis
16.
Nicotinamide adenine dinucleotide
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Nicotinamide adenine dinucleotide is a coenzyme found in all living cells. The compound is a dinucleotide, because it consists of two nucleotides joined through their phosphate groups, one nucleotide contains an adenine base and the other nicotinamide. Nicotinamide adenine dinucleotide exists in two forms, an oxidized and reduced form abbreviated as NAD+ and NADH respectively, in metabolism, nicotinamide adenine dinucleotide is involved in redox reactions, carrying electrons from one reaction to another. The coenzyme is, therefore, found in two forms in cells, NAD+ is an oxidizing agent – it accepts electrons from other molecules and becomes reduced and this reaction forms NADH, which can then be used as a reducing agent to donate electrons. These electron transfer reactions are the function of NAD. However, it is used in other cellular processes, the most notable one being a substrate of enzymes that add or remove chemical groups from proteins. Because of the importance of these functions, the involved in NAD metabolism are targets for drug discovery. In organisms, NAD can be synthesized from simple building-blocks from the amino acids tryptophan or aspartic acid, in an alternative fashion, more complex components of the coenzymes are taken up from food as the vitamin called niacin. Similar compounds are released by reactions that break down the structure of NAD and these preformed components then pass through a salvage pathway that recycles them back into the active form. Some NAD is also converted into nicotinamide adenine dinucleotide phosphate, the chemistry of this related coenzyme is similar to that of NAD, nicotinamide adenine dinucleotide, like all dinucleotides, consists of two nucleosides joined by a pair of bridging phosphate groups. The nucleosides each contain a ring, one with adenine attached to the first carbon atom. The nicotinamide moiety can be attached in two orientations to this carbon atom. Because of these two structures, the compound exists as two diastereomers. It is the diastereomer of NAD+ that is found in organisms. These nucleotides are joined together by a bridge of two groups through the 5 carbons. In metabolism, the compound accepts or donates electrons in redox reactions, such reactions involve the removal of two hydrogen atoms from the reactant, in the form of a hydride ion, and a proton. The proton is released into solution, while the reductant RH2 is oxidized, the midpoint potential of the NAD+/NADH redox pair is −0.32 volts, which makes NADH a strong reducing agent. The reaction is reversible, when NADH reduces another molecule and is re-oxidized to NAD+
17.
Fermentation
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Fermentation is a metabolic process that converts sugar to acids, gases, or alcohol. It occurs in yeast and bacteria, and also in oxygen-starved muscle cells, Fermentation is also used more broadly to refer to the bulk growth of microorganisms on a growth medium, often with the goal of producing a specific chemical product. French microbiologist Louis Pasteur is often remembered for his insights into fermentation, the science of fermentation is known as zymology. Fermentation takes place when the transport chain is unusable. In this case it becomes the primary means of ATP production. Fermentation turns NADH and pyruvate produced in glycolysis into NAD+. In the presence of O2, NADH and pyruvate are used to generate ATP in respiration and this is called oxidative phosphorylation, and it generates much more ATP than glycolysis alone. For that reason, cells generally benefit from avoiding fermentation when oxygen is available, the exception being obligate anaerobes which cannot tolerate oxygen. The first step, glycolysis, is common to all fermentation pathways, two ADP molecules and two Pi are converted to two ATP and two water molecules via substrate-level phosphorylation. Two molecules of NAD+ are also reduced to NADH, in oxidative phosphorylation the energy for ATP formation is derived from an electrochemical proton gradient generated across the inner mitochondrial membrane via the electron transport chain. Humans have used fermentation to produce drinks and beverages since the Neolithic age, Fermentation can even occur within the stomachs of animals, such as humans. To many people, fermentation simply means the production of alcohol, grains and fruits are fermented to produce beer, if a food soured, one might say it was off or fermented. Here are some definitions of fermentation and they range from informal, general usage to more scientific definitions. Preservation methods for food via microorganisms, any process that produces alcoholic beverages or acidic dairy products. Any large-scale microbial process occurring with or without air, any energy-releasing metabolic process that takes place only under anaerobic conditions. Fermentation does not necessarily have to be carried out in an anaerobic environment, for example, even in the presence of abundant oxygen, yeast cells greatly prefer fermentation to aerobic respiration, as long as sugars are readily available for consumption. The antibiotic activity of hops also inhibits aerobic metabolism in yeast, Fermentation reacts NADH with an endogenous, organic electron acceptor. Usually this is formed from the sugar during the glycolysis step. Sugars are the most common substrate of fermentation, and typical examples of products are ethanol, lactic acid, carbon dioxide
18.
Gluconeogenesis
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Gluconeogenesis is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. From breakdown of proteins, these substrates include glucogenic amino acids, from breakdown of lipids, they include glycerol, gluconeogenesis is one of several main mechanisms used by humans and many other animals to maintain blood glucose levels, avoiding low levels. Other means include the degradation of glycogen, fatty acid breakdown, gluconeogenesis is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis takes place mainly in the liver and, to a lesser extent, in ruminants, this tends to be a continuous process. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, the process is highly endergonic until it is coupled to the hydrolysis of ATP or GTP, effectively making the process exergonic. For example, the leading from pyruvate to glucose-6-phosphate requires 4 molecules of ATP and 2 molecules of GTP to proceed spontaneously. Gluconeogenesis is often associated with ketosis, gluconeogenesis is also a target of therapy for type 2 diabetes, such as the antidiabetic drug, metformin, which inhibits glucose formation and stimulates glucose uptake by cells. In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, in humans the main gluconeogenic precursors are lactate, glycerol, alanine and glutamine. Altogether, they account for over 90% of the overall gluconeogenesis, other glucogenic amino acids as well as all citric acid cycle intermediates, the latter through conversion to oxaloacetate, can also function as substrates for gluconeogenesis. In ruminants, propionate is the principal gluconeogenic substrate, lactate is transported back to the liver where it is converted into pyruvate by the Cori cycle using the enzyme lactate dehydrogenase. Pyruvate, the first designated substrate of the pathway, can then be used to generate glucose. Transamination or deamination of amino acids facilitates entering of their carbon skeleton into the cycle directly, whether even-chain fatty acids can be converted into glucose in animals has been a longstanding question in biochemistry. It is known that odd-chain fatty acids can be oxidized to yield propionyl-CoA, a precursor for succinyl-CoA, in plants, specifically seedlings, the glyoxylate cycle can be used to convert fatty acids into the primary carbon source of the organism. The glyoxylate cycle produces four-carbon dicarboxylic acids that can enter gluconeogenesis, in 1995, researchers identified the glyoxylate cycle in nematodes. In addition, the glyoxylate enzymes malate synthase and isocitrate lyase have been found in animal tissues, genes coding for malate synthase have been identified in other metazoans including arthropods, echinoderms, and even some vertebrates. Mammals found to possess these genes include monotremes and marsupials but not placental mammals, genes for isocitrate lyase are found only in nematodes, in which, it is apparent, they originated in horizontal gene transfer from bacteria. The existence of cycles in humans has not been established. However, carbon-14 has been shown to end up in glucose when it is supplied in fatty acids
19.
Glycogenesis
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Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains of glycogen for storage. Glucose is converted into glucose-6-phosphate by the action of glucokinase or hexokinase, glucose-6-phosphate is converted into glucose-1-phosphate by the action of phosphoglucomutase, passing through the obligatory intermediate glucose-1, 6-bisphosphate. Glucose-1-phosphate is converted into UDP-glucose by the action of the enzyme UDP-glucose pyrophosphorylase, pyrophosphate is formed, which is later hydrolysed by pyrophosphatase into two phosphate molecules. Glycogenin, a homodimer, has a residue on each subunit that serves as the anchor for the reducing end of glycogen. Initially, about eight UDP-glucose molecules are added to each tyrosine residue by glycogenin, one of the main forms of control is the varied phosphorylation of glycogen synthase and glycogen phosphorylase. This is regulated by enzymes under the control of hormonal activity, as such, there are many different possible effectors when compared to allosteric systems of regulation. Glycogen phosphorylase is activated by phosphorylation, whereas glycogen synthase is inhibited, Glycogen phosphorylase is converted from its less active b form to an active a form by the enzyme phosphorylase kinase. This latter enzyme is activated by protein kinase A and deactivated by phosphoprotein phosphatase-1. Protein kinase A itself is activated by the hormone adrenaline, epinephrine binds to a receptor protein that activates adenylate cyclase. Returning to glycogen phosphorylase, the less active b form can itself be activated without the conformational change, 5AMP acts as an allosteric activator, whereas ATP is an inhibitor, as already seen with phosphofructokinase control, helping to change the rate of flux in response to energy demand. Epinephrine not only activates glycogen phosphorylase but also inhibits glycogen synthase and this amplifies the effect of activating glycogen phosphorylase. This inhibition is achieved by a mechanism, as protein kinase A acts to phosphorylate the enzyme. This is known as reciprocal control. Refer to glycolysis for further information of the regulation of glycogenesis, insulin has an antagonistic effect to epinephrine signaling via the beta-adrenergic receptor. When insulin binds to its receptor, it results in the activation of Akt which in turn activates Phosphodiesterase, calcium ions or cyclic AMP act as secondary messengers. This is an example of negative control, the calcium ions activate phosphorylase kinase. This activates glycogen phosphorylase and inhibits glycogen synthase, glycogenolysis Glycogen synthase Glycogen storage disease
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